Hydrophobic docking: A proposed enhancement to molecular recognition techniques

Vakser, Ilya A.; Aflalo, Claude

doi:10.1002/prot.340200405

Cited by 180 publications

(138 citation statements)

References 32 publications

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“…nantly hydrophobic residues and constitutes a site for interaction with the P domains, whereas the corresponding residues on the surface of the globular subtilisin molecule are hydrophilic. Indeed, analysis of protein-protein interfaces distinguishes the significant contribution of steric contacts between hydrophobic amino acid residues (46)(47)(48). Moreover, surface hydrophobicity can be used to identify regions of a protein surface most likely to interact with a binding ligand (47).…”

Section: The Catalytic and P Domains Interact Through Hydrophobic Patmentioning

confidence: 99%

A model for the structure of the P domains in the subtilisin-like prohormone convertases

Lipkind

Zhou

Steiner

1998

Proc. Natl. Acad. Sci. U.S.A.

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The proprotein convertases are a family of at least seven calcium-dependent endoproteases that process a wide variety of precursor proteins in the secretory pathway. All members of this family possess an N-terminal proregion, a subtilisin-like catalytic module, and an additional downstream well-conserved region of Ϸ150 amino acid residues, the P domain, which is not found in any other subtilase. The pro and catalytic domains cannot be expressed in the absence of the P domains; their thermodynamic instability may be attributable to the presence of large numbers of negatively charged Glu and Asp side chains in the substrate binding region for recognition of multibasic residue cleavage sites. Based on secondary structure predictions, we here propose that the P domains consist of 8-stranded ␤-barrels with well-organized inner hydrophobic cores, and therefore are independently folded components of the proprotein convertases. We hypothesize further that the P domains are integrated through strong hydrophobic interactions with the catalytic domains, conferring structural stability and regulating the properties and activity of the convertases. A molecular model of these interdomain interactions is proposed in this report.Most prohormones and neuroendocrine peptide precursors, including proopiomelanocortin, proinsulin, and proglucagon, are processed by specific cellular enzymes-prohormone convertases-through the selective endoproteolytic cleavage at dibasic sites, usually Lys-Arg2 and Arg-Arg2 (1-4). Over the last decade a family of precursor processing endoproteases has been discovered, which includes the yeast prohormone processing enzyme kex2 or kexin (5, 6), the mammalian endoproteinases furin (subtilisin-like proprotein convertase 1; SPC1) (7), PACE4 (SPC4) (8), and the prohormone convertases PC2 (SPC2) (9, 10), PC1͞PC3 (SPC3) (11, 12), PC4 (SPC5) (13), PC5͞PC6 (SPC6) (14), and PC7͞PC8͞LPC (SPC7) (15-17). The core specificity of all these enzymes-paired basic amino acids-is further enhanced by the presence of additional basic residues at the P4 and further upstream sites (1, 3).When kexin was cloned and sequenced (5), it was found to contain a catalytic domain homologous to that of the bacterial subtilisins. Amino acid sequence alignments of all the mammalian convertases and kexin have shown a very high degree of similarity in their catalytic domains (18,19). The most significant difference between the subtilisins and the catalytic domains of the SPCs is the large increase in the number of negatively charged residues (Glu and Asp) in the substrate binding region relative to the subtilisins, a feature that probably contributes to the great selectivity of this family of enzymes for substrates containing multiple basic residues (1,20).Although these proteases all possess catalytic domains similar to the bacterial subtilisins, no tertiary structural data from x-ray analysis are available at this time. However, molecular modeling of the catalytic domains of furin (19) and SPC3͞ SPC1 (21), based on the known spati...

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Section: The Catalytic and P Domains Interact Through Hydrophobic Patmentioning

confidence: 99%

A model for the structure of the P domains in the subtilisin-like prohormone convertases

Lipkind

Zhou

Steiner

1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Comparisons of the partitioning in the presence of a nonpolar group with that in the presence of the same group carrying a charge (e& COO-or NH3+), or a polar group ( e g , OH), or an unsaturated moiety, has allowed characterization of the binding site (Shanbhag, 1994). Theoretical calculations have shown that a high degree of complementarity between hydrophobic groups and the presence of hydrophobic patches on the surfaces of proteins is correlated with protein binding sites (Korn & Burnett, 1991;Vakser & Aflalo, 1994;Young et al, 1994). These indicate a higher density of hydrophobic atoms at protein-protein interfaces compared with the expected based on overall surface atoms.…”

mentioning

confidence: 99%

Studies of protein‐protein interfaces: A statistical analysis of the hydrophobic effect

Tsai¹,

Lin²,

Wolfson³

et al. 1997

Protein Science

395

320

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Data sets of 362 structurally nonredundant protein-protein interfaces and of 57 symmetry-related oligomeric interfaces have been used to explore whether the hydrophobic effect that guides protein folding is also the main driving force for protein-protein associations. The buried nonpolar surface area has been used to measure the hydrophobic effect. Our analysis indicates that, although the hydrophobic effect plays a dominant role in protein-protein binding, it is not as strong as that observed in the interior of protein monomers. Comparison of the interiors of the monomers with those of the interfaces reveals that, in general, the hydrophobic amino acids are more frequent in the interior of the monomers than in the interior of the protein-protein interfaces. On the other hand, a higher proportion of charged and polar residues are buried at the interfaces, suggesting that hydrogen bonds and ion pairs contribute more to the stability of protein binding than to that of protein folding. Moreover, comparison of the interior of the interfaces to protein surfaces indicates that the interfaces are poorer in polarkharged than the surfaces and are richer in hydrophobic residues. The interior of the interfaces appears to constitute a compromise between the stabilization contributed by the hydrophobic effect on the one hand and avoiding patches on the protein surfaces that are too hydrophobic on the other. Such patches would be unfavorable for the unassociated monomers in solution. We conclude that, although the types of interactions are similar between protein-protein interfaces and single-chain proteins overall, the contribution of the hydrophobic effect to protein-protein associations is not as strong as to protein folding. This implies that packing patterns and interatom, or interresidue, pairwise potential functions, derived from monomers, are not ideally suited to predicting and assessing ligand associations or design. These would perform adequately only in cases where the hydrophobic effect at the binding site is substantial.

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“…Volumes of assigned NOESY cross-peaks were converted into 668 proton-proton upper distance limits by the program CALIBA (20) Protein-docking simulations were done with the program GRAMM (v. 1.03) (24) using a standard hydrophobic docking protocol (25). This program employs a geometric recognition algorithm performing an exhaustive six-dimensional search through relative translations and rotations of two molecules in order to provide maximal surface complementarity.…”

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confidence: 99%

A Helical Region in the C Terminus of Small-conductance Ca2+-activated K+ Channels Controls Assembly with Apo-calmodulin

Wissmann¹,

Bildl²,

Neumann³

et al. 2002

Journal of Biological Chemistry

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Small conductance Ca2؉ -activated potassium (SK) channels underlie the afterhyperpolarization that follows the action potential in many types of central neurons. SK channels are voltage-independent and gated solely by intracellular Ca 2؉ in the submicromolar range. This high affinity for Ca 2؉ results from Ca 2؉ -independent association of the SK ␣-subunit with calmodulin (CaM), a property unique among the large family of potassium channels. Here we report the solution structure of the calmodulin binding domain (CaMBD, residues 396 -487 in rat SK2) of SK channels using NMR spectroscopy. The CaMBD exhibits a helical region between residues 423-437, whereas the rest of the molecule lacks stable overall folding. Disruption of the helical domain abolishes constitutive association of CaMBD with Ca 2؉ -free CaM, and results in SK channels that are no longer gated by Ca 2؉ . The results show that the Ca 2؉ -independent CaM-CaMBD interaction, which is crucial for channel function, is at least in part determined by a region different in sequence and structure from other CaMinteracting proteins.

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Hydrophobic docking: A proposed enhancement to molecular recognition techniques

Cited by 180 publications

References 32 publications

A model for the structure of the P domains in the subtilisin-like prohormone convertases

A model for the structure of the P domains in the subtilisin-like prohormone convertases

Studies of protein‐protein interfaces: A statistical analysis of the hydrophobic effect

A Helical Region in the C Terminus of Small-conductance Ca2+-activated K+ Channels Controls Assembly with Apo-calmodulin

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